The present invention comprises a new class of compounds useful in treating diseases, such as TNF-xcex1, IL-1xcex2, IL-6 and/or IL-8 mediated diseases and other maladies, such as pain and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. This invention also relates to intermediates and processes useful in the preparation of such compounds.
Interleukin-1 (IL-1) and Tumor Necrosis Factor xcex1 (TNF-xcex1) are pro-inflammatory cytokines secreted by a variety of cells, including monocytes and macrophages, in response to many inflammatory stimuli (e.g., lipopolysaccharidexe2x80x94LPS) or external cellular stress (e.g., osmotic shock and peroxide).
Elevated levels of TNF-xcex1 and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; Pagets disease; osteophorosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic xcex2 cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn""s disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter""s syndrome; type I and type II diabetes; bone resorption diseases; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpes zoster are also exacerbated by TNF-xcex1.
It has been reported that TNF-xcex1 plays a role in head trauma, stroke, and ischemia. For instance, in animal models of head trauma (rat), TNF-xcex1 levels increased in the contused hemisphere (Shohami et al., J. Cereb. Blood Flow Metab. 14, 615 (1994)). In a rat model of ischemia wherein the middle cerebral artery was occluded, the levels of TNF-xcex1 mRNA of TNF-xcex1 increased (Feurstein et al., Neurosci. Lett. 164, 125 (1993)). Administration of TNF-xcex1 into the rat cortex has been reported to result in significant neutrophil accumulation in capillaries and adherence in small blood vessels. TNF-xcex1 promotes the infiltration of other cytokines (IL-xcex2, IL-6) and also chemokines, which promote neutrophil infiltration into the infarct area (Feurstein, Stroke 25, 1481 (1994)). TNF-xcex1 has also been implicated to play a role in type II diabetes (Endocrinol. 130, 43-52, 1994; and Endocrinol. 136, 1474-1481, 1995).
TNF-xcex1 appears to play a role in promoting certain viral life cycles and disease states associated with them. For instance, TNF-xcex1 secreted by monocytes induced elevated levels of HIV expression in a chronically infected T cell clone (Clouse et al., J. Immunol. 142, 431 (1989)). Lahdevirta et al., (Am. J. Med. 85, 289 (1988)) discussed the role of TNF-xcex1 in the HIV associated states of cachexia and muscle degradation.
TNF-xcex1 is upstream in the cytokine cascade of inflammation. As a result, elevated levels of TNF-xcex1 may lead to elevated levels of other inflammatory and proinflammatory cytokines, such as IL-1, IL-6, and IL-8.
Elevated levels of IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn""s disease; ulcerative colitis; anaphylaxis; muscle degeneration; cachexia; Reiter""s syndrome; type I and type II diabetes; bone resorption diseases; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock; and toxic shock syndrome. Viruses sensitive to TNF-xcex1 inhibition, e.g., HIV-1, HIV-2, HIV-3, are also affected by IL-1.
TNF-xcex1 and IL-1 appear to play a role in pancreatic xcex2 cell destruction and diabetes. Pancreatic xcex2 cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic xcex2 cells often accompanies type I diabetes. Pancreatic xcex2 cell functional abnormalities may occur in patients with type II diabetes. Type II diabetes is characterized by a functional resistance to insulin. Further, type II diabetes is also often accompanied by elevated levels of plasma glucagon and increased rates of hepatic glucose production. Glucagon is a regulatory hormone that attenuates liver gluconeogenesis inhibition by insulin. Glucagon receptors have been found in the liver, kidney and adipose tissue. Thus glucagon antagonists are useful for attenuating plasma glucose levels (WO 97/16442, incorporated herein by reference in its entirety). By antagonizing the glucagon receptors, it is thought that insulin responsiveness in the liver will improve, thereby decreasing gluconeogenesis and lowering the rate of hepatic glucose production.
In rheumatoid arthritis models in animals, multiple intra-articular injections of IL-1 have led to an acute and destructive form of arthritis (Chandrasekhar et al., Clinical Immunol Immunopathol. 55, 382 (1990)). In studies using cultured rheumatoid synovial cells, IL-1 is a more potent inducer of stromelysin than is TNF-xcex1 (Firestein, Am. J. Pathol. 140, 1309 (1992)). At sites of local injection, neutrophil, lymphocyte, and monocyte emigration has been observed. The emigration is attributed to the induction of chemokines (e.g., IL-8), and the up-regulation of adhesion molecules (Dinarello, Eur. Cytokine Netw. 5, 517-531 (1994)).
IL-1 also appears to play a role in promoting certain viral life cycles. For example, cytokine-induced increase of HIV expression in a chronically infected macrophage line has been associated with a concomitant and selective increase in IL-1 production (Folks et al., J. Immunol. 136, 40 (1986)). Beutler et al. (J. Immunol. 135, 3969 (1985)) discussed the role of IL-1 in cachexia. Baracos et al. (New Eng. J. Med. 308, 553 (1983)) discussed the role of IL-1 in muscle degeneration.
In rheumatoid arthritis, both IL-1 and TNF-xcex1 induce synoviocytes and chondrocytes to produce collagenase and neutral proteases, which leads to tissue destruction within the arthritic joints. In a model of arthritis (collagen-induced arthritis (CIA) in rats and mice), intra-articular administration of TNF-xcex1 either prior to or after the induction of CIA led to an accelerated onset of arthritis and a more severe course of the disease (Brahn et al., Lymphokine Cytokine Res. 11, 253 (1992); and Cooper, Clin. Exp. Immunol. 898, 244 (1992)).
IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into sites of inflammation or injury (e.g., ischemia) is mediated by the chemotactic nature of IL-8, including, but not limited to, the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the chemotaxis effect on neutrophils, IL-8 also has the ability to activate neutrophils. Thus, reduction in IL-8 levels may lead to diminished neutrophil infiltration.
Several approaches have been taken to block the effect of TNF-xcex1. One approach involves using soluble receptors for TNF-xcex1 (e.g., TNFR-55 or TNFR-75), which have demonstrated efficacy in animal models of TNF-xcex1-mediated disease states. A second approach to neutralizing TNF-xcex1 using a monoclonal antibody specific to TNF-xcex1, cA2, has demonstrated improvement in swollen joint count in a Phase II human trial of rheumatoid arthritis (Feldmann et al., Immunological Reviews, pp. 195-223 (1995)). These approaches block the effects of TNF-xcex1 and IL-1 by either protein sequestration or receptor antagonism.
U.S. Pat. No. 5,100,897, incorporated herein by reference in its entirety, describes pyrimidinone compounds useful as angiotensin II antagonists wherein one of the pyrimidinone ring nitrogen atoms is substituted with a substituted phenylmethyl or phenethyl radical.
U.S. Pat. No. 5,162,325, incorporated herein by reference in its entirety, describes pyrimidinone compounds useful as angiotensin II antagonists wherein one of the pyrimidinone ring nitrogen atoms is substituted with a substituted phenylmethyl radical.
EP 481448, incorporated herein by reference in its entirety, describes pyrimidinone compounds useful as angiotensin II antagonists wherein one of the pyrimidinone ring nitrogen atoms is substituted with a substituted phenyl, phenylmethyl or phenethyl radical.
CA 2,020,370, incorporated herein by reference in its entirety, describes pyrimidinone compounds useful as angiotensin II antagonists wherein one of the pyrimidinone ring nitrogen atoms is substituted with a substituted biphenylaliphatic hydrocarbon radical.
The present invention comprises a new class of compounds useful in the prophylaxis and treatment of diseases, such as TNF-xcex1, IL-1xcex2, IL-6 and/or IL-8 mediated diseases and other maladies, such as pain and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds, methods for the prophylaxis and treatment of TNF-xcex1, IL-1xcex2, IL-6 and/or IL-8 mediated diseases, such as inflammatory, pain and diabetes diseases, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
The compounds of the invention are represented by the following general structure: 
wherein the dashed lines represent a double bond between C(R) and V or W (i.e., xe2x80x94Vxe2x95x90C(R)xe2x80x94 or xe2x80x94Wxe2x95x90C(R)xe2x80x94) and V, W, X, R, R11 and R12 are defined below.
The foregoing merely summarizes certain aspects of the invention and is not intended, nor should it be construed, as limiting the invention in any way. All patents and other publications recited herein are hereby incorporated by reference in their entirety.
In accordance with the present invention, there is provided compounds of the formula: 
or a pharmaceutically acceptable salt thereof, wherein
X is O, S or NR5; preferably, X is O or S; and most preferably, X is O; 
xe2x80x83provided that the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in xe2x80x94VC(R)Wxe2x80x94 is 0-3, preferably, 0-2, most preferably, 0-1;
a first preferred subgroup of 
a second preferred subgroup of 
a third preferred subgroup of 
more preferably, 
most preferably, 
U is NR21 or CHR21; preferably, U is NR21;
n is an integer of 1-3;
R1 and R2 are each independently xe2x80x94Y or xe2x80x94Zxe2x80x94Y, and R3 and R4 are each independently xe2x80x94Zxe2x80x94Y or R3 is a hydrogen radical; provided that R4 is other than a substituted-aryl, (substituted-aryl)methyl or (substituted-aryl)ethyl radical, and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each xe2x80x94Y and xe2x80x94Zxe2x80x94Y is 0-3; preferably, 0-2; more preferably, 0-1;
preferably, R2 is a radical of hydrogen, C1-C4 alkyl, halo, cyano, hydroxy, C1-C4 alkoxy, C1-C2 haloalkoxy of 1-3 halo radicals, C1-C4 alkylthio, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino or C1-C2 haloalkyl of 1-3 halo radicals; more preferably, R2 is a radical of hydrogen, C1-C4 alkyl, halo, cyano, hydroxy, C1-C4 alkoxy, trifluoromethoxy or trifluoromethyl; most preferably, R2 is a hydrogen radical;
preferably, R3 is a hydrogen radical or
(1) C1-C8 alkyl or C2-C8 alkenyl radical optionally substituted by (a) 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals; or
(2) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals;
more preferably, R3 is a hydrogen radical or
(1) C1-C8 alkyl radical optionally substituted by 1-2 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, hydroxy, C1-C4 alkoxy or aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals; or
(2) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals;
more preferably, R3 is a hydrogen radical or C1-C8 alkyl radical optionally substituted by 1-2 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, hydroxy, C1-C4 alkoxy or aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals;
more preferably, R3 is a radical of hydrogen or C1-C4 alkyl;
more preferably, R3 is a hydrogen, methyl or ethyl radical;
preferably, R4 is
(1) C1-C8 alkyl or C2-C8 alkenyl radical optionally substituted by (a) 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals; or
(2) heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals;
more preferably, R4 is
(1) C1-C8 alkyl radical optionally substituted by 1-2 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, hydroxy, C1-C4 alkoxy or aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals; or
(2) heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals;
more preferably, R4 is a C1-C8 alkyl radical optionally substituted by 1-2 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, hydroxy, C1-C4 alkoxy or aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals;
more preferably, R4 is a C1-C4 alkyl radical; most
preferably, R4 is a methyl or ethyl radical;
wherein each Z is independently a
(1) alkyl, alkenyl or alkynyl radical optionally substituted by (a) 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, halo, alkyl or haloalkyl;
(2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; or
(3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl;
preferably, each Z is independently a
(1) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radical optionally substituted by (a) 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
(3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each Z is independently a
(1) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radical optionally substituted by (a) 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
(3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each Z is independently a
(1) C1-C8 alkyl or C2-C8 alkenyl radical optionally substituted by (a) 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(C1-C4 alkyl)amino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkyl radicals; or
(3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals;
more preferably, each Z is independently a
(1) C1-C4 alkyl or C2-C5 alkenyl radical optionally substituted by (a) 1-3 radicals of amino, di-(C1-C2 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C2 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl or trifluoromethyl radicals;
(2) heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(C1-C2 alkyl)amino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio or C1-C4 alkyl radicals; or
(3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
more preferably, each Z is independently a
(1) C1-C4 alkyl or C2-C5 alkenyl radical optionally substituted by (a) 1-3 radicals of amino, di-(C1-C2 alkyl)amino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio or halo, and (b) 1-2 radicals of aryl or heteroaryl optionally substituted by 1-2 radicals of amino, di-(C1-C2 alkyl)amino, acetamido, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, halo, C1-C4 alkyl or trifluoromethyl radicals; or
(2) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
more preferably, each Z is independently a C1-C4 alkyl radical optionally substituted by 1-2 radicals of amino, di-(C1-C2 alkyl)amino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, halo or aryl or heteroaryl optionally substituted by 1-2 radicals of hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, halo, C1-C4 alkyl or trifluoromethyl radicals; and
most preferably, each Z is independently a C1-C4 alkyl radical optionally substituted by 1-2 radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy, methoxy, methylthio or halo radicals;
each Y is independently a
(1) hydrogen radical;
(2) halo or nitro radical;
(3) xe2x80x94C(O)xe2x80x94R20 or xe2x80x94C(NR5)xe2x80x94NR5R21 radical;
(4) xe2x80x94OR21, xe2x80x94Oxe2x80x94C(O)xe2x80x94R21, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR5R21 or xe2x80x94Oxe2x80x94C(O)xe2x80x94NR22xe2x80x94S(O)2xe2x80x94R20 radical;
(5) xe2x80x94SR21, xe2x80x94S(O)xe2x80x94R20, xe2x80x94S(O)2xe2x80x94R20, xe2x80x94S(O)2xe2x80x94NR5R21, xe2x80x94S(O)2xe2x80x94NR22xe2x80x94C(O)xe2x80x94R21, xe2x80x94S(O)2xe2x80x94NR22xe2x80x94C(O)xe2x80x94OR20 or xe2x80x94S(O)2xe2x80x94NR22xe2x80x94C(O)xe2x80x94NR5R21 radical; or
(6) xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94OR20, xe2x80x94NR22xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(NR5)xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94NR22xe2x80x94S(O)2xe2x80x94NR5R21 radical;
preferably, each Y is independently a
(1) hydrogen radical;
(2) halo radical;
(3) xe2x80x94C(O)xe2x80x94R20 or xe2x80x94C(NR5)xe2x80x94NRSR21 radical;
(4) xe2x80x94OR21, xe2x80x94Oxe2x80x94C(O)xe2x80x94R21 or xe2x80x94Oxe2x80x94C(O)xe2x80x94NR5R21 radical;
(5) xe2x80x94SR21, xe2x80x94S(O)xe2x80x94R20, xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94S(O)2xe2x80x94NR5R21 radical; or
(6) xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94OR20, xe2x80x94NR22xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(NR5)xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94NR22xe2x80x94S(O)2xe2x80x94NR5R21 radical;
more preferably, each Y is independently a
(1) hydrogen radical;
(2) xe2x80x94C(O)xe2x80x94R20 radical;
(3) xe2x80x94OR21, xe2x80x94SR21, xe2x80x94S(O)xe2x80x94R20, xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94S(O)2xe2x80x94NR5R21 radical; or
(4) xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94OR20, xe2x80x94NR22xe2x80x94C(O)xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94NR22xe2x80x94S(O)2xe2x80x94NR5R21 radical;
more preferably, each Y is independently a
(1) hydrogen radical;
(2) xe2x80x94C(O)xe2x80x94R20 radical;
(3) xe2x80x94OR21, xe2x80x94SR21, xe2x80x94S(O)xe2x80x94R20, xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94S(O)2xe2x80x94NR5R21 radical; or
(4) xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94R21 or xe2x80x94NR22xe2x80x94S(O)2xe2x80x94R20 radical;
more preferably, each Y is independently a
(1) xe2x80x94C(O)xe2x80x94R20 radical;
(2) xe2x80x94OR21, xe2x80x94SR21, xe2x80x94S(O)xe2x80x94R20, xe2x80x94S(O)2xe2x80x94R20 or xe2x80x94S(O)2xe2x80x94NR5R21 radical; or
(3) xe2x80x94NR5R21, xe2x80x94NR22xe2x80x94C(O)xe2x80x94R21 or xe2x80x94NR22xe2x80x94S(O)2xe2x80x94R20 radical.
most preferably, each Y is independently a xe2x80x94OR21, xe2x80x94SR21 or xe2x80x94NR5R21 radical;
wherein each R5 is independently
(1) hydrogen radicals;
(2) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, xe2x80x94SO3H or halo; or
(3) aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl;
preferably, each R5 is independently
(1) hydrogen radicals;
(2) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, xe2x80x94SO3H or halo; or
(3) aryl, heteroaryl, aryl-C1-C4-alkyl, heteroaryl-C1-C4-alkyl, heterocyclyl, heterocyclyl-C1-C4-alkyl, C3-C8 cycloalkyl or C3-C8-cycloalkyl-C1-C4-alkyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R5 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl, C2-C5 alkenyl or C2-C5 alkynyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, xe2x80x94SO3H or halo; or
(3) aryl, heteroaryl, aryl-C1-C4-alkyl, heteroaryl-C1-C4-alkyl, heterocyclyl, heterocyclyl-C1-C4-alkyl, C3-C8 cycloalkyl or C3-C8-cycloalkyl-C1-C4-alkyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R5 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl or C2-C5 alkenyl radicals optionally substituted by 1-3 radicals of amino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, xe2x80x94SO3H or halo; or
(3) phenyl-C1-C2-alkyl, heteroaryl-C1-C2-alkyl, heterocyclyl-C1-C2-alkyl or C3-C6-cycloalkyl-C1-C2-alkyl radicals optionally substituted by 1-3 radicals of amino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals;
more preferably, each R5 is independently
(1) hydrogen radical;
(2) C1-C4 alkyl radical optionally substituted by 1-3 radicals of amino, di-(C1-C2-alkyl)amino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio or halo; or
(3) phenyl-C1-C2-alkyl, heteroaryl-C1-C2-alkyl, heterocyclyl-C1-C2-alkyl or C3-C6-cycloalkyl-C1-C2-alkyl radicals optionally substituted by 1-3 radicals of amino, di-(C1-C2-alkyl)amino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, methoxy, methylthio, C1-C4 alkyl or trifluoromethyl radicals;
more preferably, each R5 is independently
(1) hydrogen radical;
(2) C1-C4 alkyl radical optionally substituted by 1-3 halo radicals; or
(3) phenyl-C1-C2-alkyl or heteroaryl-C1-C2-alkyl, radicals optionally substituted by 1-3 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, methyl or trifluoromethyl radicals;
more preferably, each R5 is independently hydrogen or C1-C4 alkyl radical; and most preferably, each R5 is a hydrogen radical;
wherein each R20 is independently
(1) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, N-(alkoxycarbonyl)-N-(alkyl)amino, aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo or aralkoxy, aralkylthio, aralkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkanoyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo, alkyl or haloalkyl;
(2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; or
(3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo, azido, alkyl or haloalkyl;
preferably, each R20 is independently
(1) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-C4 alkyl)amino, aminocarbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5 alkanoyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R20 is independently
(1) C1-C8 alkyl, C2-C5 alkenyl or C2-C5 alkynyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-C4 alkyl)amino, aminocarbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5 alkanoyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
(3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R20 is independently
(1) C1-C8 alkyl or C2-C5 alkenyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-C4 alkyl)amino, aminocarbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5 alkanoyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or
(3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals;
more preferably, each R20 is independently
(1) C1-C8 alkyl or C2-C5 alkenyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-C4 alkyl)amino, aminocarbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, halo or a-ryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5 alkanoyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(C1-C4 alkyl)amino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or
(3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, acetamido, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl or trifluoromethyl radicals;
more preferably, each R20 is independently
(1) C1-C8 alkyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-C4 alkyl)amino, aminocarbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, halo or C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl or trifluoromethyl radicals;
(2) heterocyclyl radical optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or
(3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of (C1-C4 alkoxy)carbonyl, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl or trifluoromethyl radicals;
more preferably, each R20 is independently
(1) C1-C6 alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N-(methyl)amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or C5-C6 cycloalkyl, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;
(2) heterocyclyl radical optionally substituted by 1-2 radicals of hydroxy or C1-C4 alkyl; or
(3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;
more preferably, each R20 is independently
(1) C1-C6 alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N-(methyl)amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or C5-C6 cycloalkyl, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;
(2) heterocyclyl radical; or
(3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;
most preferably, each R20 is independently
(1) C1-C6 alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, hydroxy or phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;
(2) heterocyclyl radical; or
(3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;
each R21 is independently hydrogen radical or R20;
each R22 is independently
(1) hydrogen radical;
(2) alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; or
(3) heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; provided when Z is a bond and Y is xe2x80x94NR22xe2x80x94C(O)xe2x80x94NH2, then R22 is other then an optionally substituted aryl radical;
preferably, each R22 is independently
(1) hydrogen radical;
(2) C1-C4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
(3) heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; provided when Z is a bond and Y is xe2x80x94NR22xe2x80x94C(O)xe2x80x94NH2, then R22 is other then an optionally substituted aryl radical;
more preferably, each R22 is independently
(1) hydrogen radical; or
(2) C1-C4 alkyl radical optionally substituted by a radical of phenyl or heteroaryl optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals;
more preferably, each R22 is independently hydrogen or C1-C4 alkyl radical; and most preferably, each R22 is independently hydrogen or methyl radical;
R11 and R12 are each independently an aryl or heteroaryl radical optionally substituted by 1-3 radicals of
(1) R30;
(2) halo or cyano radicals;
(3) xe2x80x94C(O)xe2x80x94R30, xe2x80x94C(O)xe2x80x94OR29, xe2x80x94C(O)xe2x80x94NR31R32 or xe2x80x94C(NR31)xe2x80x94NR31R32 radicals;
(4) xe2x80x94OR29, xe2x80x94Oxe2x80x94C(O)xe2x80x94R29, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR31R32 or xe2x80x94Oxe2x80x94C(O)xe2x80x94NR33xe2x80x94S(O)2xe2x80x94R30 radicals;
(5) xe2x80x94SR29, xe2x80x94S(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR31R32, xe2x80x94S(O)2xe2x80x94NR33xe2x80x94C(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR33xe2x80x94C(O)xe2x80x94OR30 or xe2x80x94S(O)2xe2x80x94NR33xe2x80x94C(O)xe2x80x94NR31R32 radicals; or
(6) xe2x80x94NR31R32, xe2x80x94NR33xe2x80x94C(O)xe2x80x94R29, xe2x80x94NR33xe2x80x94C(O)xe2x80x94OR30, xe2x80x94NR33xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94NR33xe2x80x94C(NR31)xe2x80x94NR31R32, xe2x80x94NR33xe2x80x94S(O)2xe2x80x94R30 or xe2x80x94NR33xe2x80x94S(O) NR31R32 radicals;
provided that (1) R11 is other than a 4-pyridyl, 4-pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and (2) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R11 and R12 is 0-1;
preferably, R11 and R12 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of
(1) R30;
(2) halo or cyano radicals;
(3) xe2x80x94C(O)xe2x80x94R30, xe2x80x94C(O)xe2x80x94OR29, xe2x80x94C(O)xe2x80x94NR31R32 or xe2x80x94C(NR31)xe2x80x94NR31R32 radicals;
(4) xe2x80x94OR29, xe2x80x94Oxe2x80x94C(O)xe2x80x94R29, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR31R32 or xe2x80x94Oxe2x80x94C(O)xe2x80x94NR33xe2x80x94S(O)2xe2x80x94R30 radicals;
(5) xe2x80x94SR29, xe2x80x94S(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR31R32, xe2x80x94S(O)2xe2x80x94NR33xe2x80x94C(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR33xe2x80x94C(O)xe2x80x94OR30 or xe2x80x94S(O)2xe2x80x94NR33xe2x80x94C(O)xe2x80x94NR31R32 radicals; or
(6) xe2x80x94NR31R32, xe2x80x94NR33xe2x80x94C(O)xe2x80x94R29, xe2x80x94NR33xe2x80x94C(O)xe2x80x94OR30, xe2x80x94NR33xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94NR33xe2x80x94C(NR31)xe2x80x94NR31R32, xe2x80x94NR33xe2x80x94S(O)2xe2x80x94R30 or xe2x80x94NR33xe2x80x94S(O)2xe2x80x94NR31R32 radicals;
provided that (1) R11 is other than a 4-pyridyl, 4-pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and (2) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R11 and R12 is
more preferably, R11 and R12 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of
(1) R30;
(2) halo or cyano radicals;
(3) xe2x80x94C(O)xe2x80x94R30, xe2x80x94C(O)xe2x80x94OR29, xe2x80x94C(O)xe2x80x94NR31R32 or xe2x80x94C(NR31)xe2x80x94NR31R32 radicals; or
(4) xe2x80x94OR29, xe2x80x94SR29, xe2x80x94S(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94R30xe2x80x94S(O)2xe2x80x94NR31R32, xe2x80x94NR31R32, xe2x80x94NR33xe2x80x94C(O)xe2x80x94R29 or xe2x80x94NR33xe2x80x94C(O)xe2x80x94OR30 radicals;
more preferably, R11 is an aryl radical and R12 is a heteroaryl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of
(1) R30;
(2) halo or cyano radicals;
(3) xe2x80x94C(O)xe2x80x94R30, xe2x80x94C(O)xe2x80x94OR29, xe2x80x94C(O)xe2x80x94NR31R32 or xe2x80x94C(NR31)xe2x80x94NR31R32 radicals; or
(4) xe2x80x94OR29, xe2x80x94SR29, xe2x80x94S(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR31R32, xe2x80x94NR31R32 or xe2x80x94NR33xe2x80x94C(O)xe2x80x94R29 radicals;
more preferably, R11 is an aryl radical and R12 is a heteroaryl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of
(1) R30;
(2) halo or cyano radicals; or
(3) xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94OR29, xe2x80x94SR29, xe2x80x94S(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR31R32, xe2x80x94NR31R32 or xe2x80x94NR33xe2x80x94C(O)xe2x80x94R29 radicals;
more preferably, R11 is an aryl radical optionally substituted by 1-2 radicals of (1) R30; (2) halo or cyano radicals; or (3)xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94OR29, xe2x80x94SR29, xe2x80x94S(O)xe2x80x94R30, xe2x80x94S(O)2xe2x80x94R30, xe2x80x94S(O)2xe2x80x94NR31R32, xe2x80x94NR31R32 or xe2x80x94NR33xe2x80x94C(O)xe2x80x94R29 radicals; more preferably, R11 is an aryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; more preferably, R11 is an unsubstituted phenyl or naphthyl radical or a phenyl radical substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; and most preferably, R11 is an unsubstituted phenyl radical or a phenyl radical substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfonyl, methyl or trifluoromethyl radicals;
more preferably, R12 is a heteroaryl radical optionally substituted by 1-2 radicals of (1) R30; (2) halo or cyano radicals; or (3) xe2x80x94C(O)xe2x80x94NR31R32, xe2x80x94OR29, xe2x80x94SR29, xe2x80x94NR31R32 or xe2x80x94NR33xe2x80x94C(O)xe2x80x94R29 radicals; more preferably, R12 is a heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals; more preferably, R12 is a 4-pyridyl, 4-quinolinyl, 4-imidazolyl or 4-pyrimidinyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals; and most preferably, R12 is a 4-pyridyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals;
wherein each R30 is independently
(1) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of xe2x80x94NR31R31, xe2x80x94CO2R23, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl;
(2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or
(3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl;
preferably, each R30 is independently
(1) C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl radicals optionally substituted by 1-3 radicals of xe2x80x94NR31R31, xe2x80x94CO2R23, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
(3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R30 is independently
(1) C1-C4 alkyl radical optionally substituted by 1-3 radicals of
(a) xe2x80x94NR31R31;
(b) C1-C4 alkoxy-carbonyl or phenoxycarbonyl or phenylmethoxycarbonyl optionally substituted by 1-3 radicals of amino, alkylamino, di-(C1-C4-alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4-alkyl or trifluoromethyl; or
(c) hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, or phenyl-C1-C4-alkoxy, phenyl-C1-C4-alkylthio, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
(2) C1-C4 haloalkyl of 1-3 halo radical; or
(3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
more preferably, each R30 is independently
(1) C1-C4 alkyl radical optionally substituted by
(a) amino, C1-C4 alkylamino or di-(C1-C4-alkyl)amino radicals; or
(b) hydroxy, C1-C4 alkoxy, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
(2) C1-C2 haloalkyl of 1-3 halo radical; or
(3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
more preferably, each R30 is independently
(1) C1-C4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido, hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl or trifluoromethyl radicals;
(2) trifluoromethyl radical; or
(3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido, hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl or trifluoromethyl radicals;
more preferably, each R30 is independently
(1) C1-C4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;
(2) trifluoromethyl radical; or
(3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;
most preferably, R30 is independently
(1) C1-C4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;
(2) trifluoromethyl radical; or
(3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;
each R29 is independently hydrogen radical or R30; and most preferably, R29 is an aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;
each R31 is independently
(1) hydrogen radicals;
(2) alkyl radical optionally substituted by an cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or
(3) aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl;
preferably, each R31 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical optionally substituted by an C3-C8 cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
(3) aryl, heteroaryl, heterocyclyl or C3-C8 cycloalkyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R31 is independently
(1) hydrogen radicals; or
(2) C1-C4 alkyl radical optionally substituted by an phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or trifluoromethyl radicals;
more preferably, each R31 is independently hydrogen or C1-C4 alkyl radicals; and most preferably, each R31 is independently hydrogen, methyl or ethyl radicals;
each R32 is independently
(1) hydrogen radicals;
(2) alkyl radical optionally substituted by an cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or
(3) aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl;
preferably, each R32 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical optionally substituted by an C3-C8 cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
(3) aryl, heteroaryl, heterocyclyl or C3-C8 cycloalkyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R32 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical optionally substituted by an C3-C6 cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
(3) aryl, heteroaryl, heterocyclyl or C3-C6 cycloalkyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R32 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical optionally substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkyl or trifluoromethyl radicals; or
(3) phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkyl or trifluoromethyl radicals;
more preferably, each R32 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical or C1-C2 alkyl radical substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; or
(3) phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals;
most preferably, R32 is independently
(1) hydrogen or C1-C4 alkyl radical; or
(2) phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; and
wherein each R33 is independently
(1) hydrogen radical; or
(2) alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl;
preferably, each R33 is independently
(1) hydrogen radical; or
(2) C1-C4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R33 is independently hydrogen or C1-C4 alkyl radical; and most preferably, each R33 is independently hydrogen or methyl radical.
The compounds of this invention may have in general several asymmetric centers and are typically depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diasteromers.
Compounds of interest include the following: 
wherein R11, R12, and R1 are one of the combinations given in the following table:
wherein R11, R12, and R1 are one of the combinations given in the following table:
wherein R11, R12, and R1 are one of the combinations given in the following table:
in which R2 is H, methyl or benzyl, and R11, R12, and R1 are one of the combinations given in the following table:
Additional preferred compounds are listed in the Examples, infra.
As utilized herein, the following terms shall have the following meanings:
xe2x80x9cAlkylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain alkyl radical containing preferably 1-15 carbon atoms (C1-C15), more preferably 1-8 carbon atoms (C1-C8), even more preferably 1-6 carbon atoms (C1-C6), yet more preferably 1-4 carbon atoms (C1-C4), still more preferably 1-3 carbon atoms (C1-C3), and most preferably 1-2 carbon atoms (C1-C2). Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
xe2x80x9cHydroxyalkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above wherein at least one hydrogen radical is replaced with a hydroxyl radical, preferably 1-3 hydrogen radicals are replaced by hydroxyl radicals, more preferably 1-2 hydrogen radicals are replaced by hydroxyl radicals, and most preferably one hydrogen radical is replaced by a hydroxyl radical. Examples of such radicals include hydroxymethyl, 1-, 2-hydroxyethyl, 1-, 2-, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 1,3-dihydroxybutyl, 1,2,3,4,5,6-hexahydroxy-2-hexyl and the like.
xe2x80x9cAlkenylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds, preferably 1-2 double bonds and more preferably one double bond, and containing preferably 2-15 carbon atoms (C2-C15), more preferably 2-8 carbon atoms (C2-C8), even more preferably 2-6 carbon atoms (C2-C6), yet more preferably 2-4 carbon atoms (C2-C4), and still more preferably 2-3 carbon atoms (C2-C3). Examples of such alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like.
xe2x80x9cAlkoxyxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cOxe2x80x9d is an oxygen atom. Examples of such alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94Oxe2x80x94xe2x80x9d is an alkoxy radical as defined above and xe2x80x9cC(O)xe2x80x9d is a carbonyl radical.
xe2x80x9cAlkoxycarbonylaminoxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x9d is an alkoxycarbonyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
xe2x80x9cAlkylthioxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Sxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cSxe2x80x9d is a sulfur atom. Examples of such alkylthio radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio and the like.
xe2x80x9cAlkylsulfinylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94S(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cS(O)xe2x80x9d is a mono-oxygenated sulfur atom. Examples of such alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, iso-butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl and the like.
xe2x80x9cAlkylsulfonylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94S(O)2xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cS(O)2xe2x80x9d is a di-oxygenated sulfur atom. Examples of such alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like.
xe2x80x9cArylxe2x80x9d, alone or in combination, means a phenyl or biphenyl radical, which is optionally benzo fused or heterocyclo fused and which is optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, azido, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, N-alkylamido, N,N-dialkylamido, aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, oxo and the like. Examples of aryl radicals are phenyl, o-tolyl, 4-methoxyphenyl, 2-(tert-butoxy)phenyl, 3-methyl-4-methoxyphenyl, 2-CF3-phenyl, 2-fluorophenyl, 2-chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 3-acetamidophenyl, 2-amino-3-(aminomethyl)phenyl, 6-methyl-3-acetamidophenyl, 6-methyl-2-aminophenyl, 6-methyl-2,3-diaminophenyl, 2-amino-3-methylphenyl, 4,6-dimethyl-2-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 4-(2-methoxyphenyl)phenyl, 2-amino-1-naphthyl, 2-naphthyl, 3-amino-2-naphthyl, 1-methyl-3-amino-2-naphthyl, 2,3-diamino-1-naphthyl, 4,8-dimethoxy-2-naphthyl and the like.
xe2x80x9cAralkylxe2x80x9d and xe2x80x9carylalkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyl, 1-, 2-phenylethyl, dibenzylmethyl, hydroxyphenylmethyl, methylphenylmethyl, diphenylmethyl, dichlorophenylmethyl, 4-methoxyphenylmethyl and the like.
xe2x80x9cAralkoxyxe2x80x9d, alone or in combination, means an alkoxy radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyloxy, 1-, 2-phenylethoxy, dibenzylmethoxy, hydroxyphenylmethoxy, methylphenylmethoxy, dichlorophenylmethoxy, 4-methoxyphenylmethoxy and the like.
xe2x80x9cAralkoxycarbonylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94C(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94Oxe2x80x94xe2x80x9d is an aralkoxy radical as defined above and xe2x80x9cxe2x80x94C(O)xe2x80x94xe2x80x9d is a carbonyl radical.
xe2x80x9cAlkanoylxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94C(O)xe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cxe2x80x94C(O)xe2x80x94xe2x80x9d is a carbonyl radical. Examples of such alkanoyl radicals include acetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
xe2x80x9cAlkanoylaminoxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94C(O)xe2x80x94NHxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x94C(O)xe2x80x94xe2x80x9d is an alkanoyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
xe2x80x9cAminocarbonylxe2x80x9d, alone or in combination, means an amino substituted carbonyl (carbamoyl) radical, wherein the amino radical may optionally be mono- or di-substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like.
xe2x80x9cAminosulfonylxe2x80x9d, alone or in combination, means an amino substituted sulfonyl radical.
xe2x80x9cBenzoxe2x80x9d, alone or in combination, means the divalent radical C6H4xe2x95x90 derived from benzene. xe2x80x9cBenzo fusedxe2x80x9d forms a ring system in which benzene and a cycloalkyl or aryl group have two carbons in common, for example tetrahydronaphthylene and the like.
xe2x80x9cBicyclicxe2x80x9d as used herein is intended to include both fused ring systems,.such as naphthyl and xcex2-carbolinyl, and substituted ring systems, such as biphenyl, phenylpyridyl and diphenylpiperazinyl.
xe2x80x9cCycloalkylxe2x80x9d, alone or in combination, means a saturated or partially saturated, preferably one double bond, monocyclic, bicyclic or tricyclic carbocyclic alkyl radical, preferably monocyclic, containing preferably 5-12 carbon atoms (C5-C12), more preferably 5-10 carbon atoms (C5-C10), even more preferably 5-7 carbon atoms (C5-C7), which is optionally benzo fused or heterocyclo fused and which is optionally substituted as defined herein with respect to the definition of aryl. Examples of such cycloalkyl radicals include cyclopentyl, cyclohexyl, dihydroxycyclohexyl, ethylenedioxycyclohexyl, cycloheptyl, octahydronaphthyl, tetrahydronaphthyl, octahydroquinolinyl, dimethoxytetrahydronaphthyl, 2,3-dihydro-1H-indenyl, azabicyclo[3.2.1]octyl and the like.
xe2x80x9cHeteroatomsxe2x80x9d means nitrogen, oxygen and sulfur heteroatoms.
xe2x80x9cHeterocyclo fusedxe2x80x9d forms a ring system in which a heterocyclyl or heteroaryl group of 5-6 ring members and a cycloalkyl or aryl group have two carbons in common, for example indole, isoquinoline, tetrahydroquinoline, methylenedioxybenzene and the like.
xe2x80x9cHeterocyclylxe2x80x9d means a saturated or partially unsaturated, preferably one double bond, monocyclic or bicyclic, preferably monocyclic, heterocycle radical containing at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, nitrogen, oxygen or sulfur atom ring member and having preferably 3-8 ring members in each ring, more preferably 5-8 ring members in each ring and even more preferably 5-6 ring members in each ring. xe2x80x9cHeterocyclylxe2x80x9d is intended to include sulfone and sulfoxide derivatives of sulfur ring members and N-oxides of tertiary nitrogen ring members, and carbocyclic fused, preferably 3-6 ring carbon atoms and more preferably 5-6 ring carbon atoms, and benzo fused ring systems. xe2x80x9cHeterocyclylxe2x80x9d radicals may optionally be substituted on at least one, preferably 1-4, more preferably 1-3, even more preferably 1-2, carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, thioxo, aryl, aralkyl, heteroaryl, heteroaralkyl, amidino, N-alkylamidino, alkoxycarbonylamino, alkylsulfonylamino and the like, and/or on a secondary nitrogen atom by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, alkoxycarbonyl, heteroaralkyl, aryl or aralkyl radicals. More preferably, xe2x80x9cheterocyclylxe2x80x9d, alone or in combination, is a radical of a monocyclic or bicyclic saturated heterocyclic ring system having 5-8 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally partially unsaturated or benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals. Examples of such heterocyclyl radicals include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 4-benzyl-piperazin-1-yl, pyrimidinyl, tetrahydrofuryl, pyrazolidonyl, pyrazolinyl, pyridazinonyl, pyrrolidonyl, tetrahydrothienyl and its sulfoxide and sulfone derivatives, 2,3-dihydroindolyl, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, 2,3-dihydrobenzofuryl, benzopyranyl, methylenedioxyphenyl, ethylenedioxyphenyl and the like.
xe2x80x9cHeteroarylxe2x80x9d means a monocyclic or bicyclic, preferably monocyclic, aromatic heterocycle radical, having at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, nitrogen, oxygen or sulfur atom ring members and having preferably 5-6 ring members in each ring, which is optionally saturated carbocyclic fused, preferably 3-4 carbon atoms (C3-C4) to form 5-6 ring membered rings and which is optionally substituted as defined above with respect to the definitions of aryl. Examples of such heteroaryl groups include imidazolyl, 1-benzyloxycarbonylimidazol-4-yl, pyrrolyl, pyrazolyl, pyridyl, 3-(2-methyl)pyridyl, 3-(4-trifluoromethyl)pyridyl, pyrimidinyl, 5-(4-trifluoromethyl)pyrimidinyl, pyrazinyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, indolyl, quinolinyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolinyl, quinoxalinyl, benzothiazolyl, benzofuryl, benzimidazolyl, benzoxazolyl and the like.
xe2x80x9cHeteroaralkylxe2x80x9d and xe2x80x9cheteroarylalkyl,xe2x80x9d alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by a heteroaryl radical as defined above, such as 3-furylpropyl, 2-pyrrolyl propyl, chloroquinolinylmethyl, 2-thienylethyl, pyridylmethyl, 1-imidazolylethyl and the like.,
xe2x80x9cHalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d, alone or in combination, means fluoro, chloro, bromo or iodo radicals.
xe2x80x9cHaloalkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-3, is replaced by a halogen radical, more preferably fluoro or chloro radicals. Examples of such haloalkyl radicals include 1,1,1-trifluoroethyl, chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bis(trifluoromethyl)methyl and the like.
xe2x80x9cPharmacologically acceptable saltxe2x80x9d means a salt prepared by conventional means, and are well known by those skilled in the art. The xe2x80x9cpharmacologically acceptable saltsxe2x80x9d include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. When compounds of the invention include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the-art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. For additional examples of xe2x80x9cpharmacologically acceptable salts,xe2x80x9d see infra and Berge et al, J. Pharm. Sci. 66, 1 (1977).
xe2x80x9cCytokinexe2x80x9d means a secreted protein that affects the functions of other cells, particularly as it relates to the modulation of interactions between cells of the immune system or cells involved in the inflammatory response. Examples of cytokines include but are not limited to interleukin 1 (IL-1), preferably IL-1xcex2, interleukin 6 (IL-6), interleukin 8 (IL-8) and TNF, preferably TNF-xcex1 (tumor necrosis factor-xcex1).
xe2x80x9cTNF, IL-1, IL-6, and/or IL-8 mediated disease or disease statexe2x80x9d means all disease states wherein TNF, IL-1, IL-6, and/or IL-8 plays a role, either directly as TNF, IL-1, IL-6, and/or IL-8 itself, or by TNF, IL-1, IL-6, and/or IL-8 inducing another cytokine to be released. For example, a disease state in which IL-1 plays a major role, but in which the production of or action of IL-1 is a result of TNF, would be considered mediated by TNF.
xe2x80x9cLeaving groupxe2x80x9d generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
xe2x80x9cProtecting groupxe2x80x9d generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy,. amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples of aralkyl include, but are not limited to, benzyl, orthomethylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals, preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloro acetyl, phthaloyl and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings. In addition, the heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl. Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like. Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkyl groups are also sutiable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane and diphenylmethylsilyl. Silylation of an amino groups provide mono- or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a N,N,O-tri-silyl derivative. Removal of the silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium flouride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art. Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine. Carboxy protecting group, such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydroylsis and hydrogenolysis conditions well known to those skilled in the art.
The symbols used above have the following meanings: 
Prodrugs of the compounds of this invention are also contemplated by this invention. A prodrug is an active or inactive compound that is modified chemically through in vivo physicological action, such as hydrolysis, metabolism and the like, into a compound of this invention following adminstration of the prodrug to a patient. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
Compounds according to the invention can be synthesized according to one or more of the following methods. It should be noted that the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry about a group is (S) or (R). In addition, the compounds having one stereochemistry (e.g., (R)) can often be utilized to produce those having opposite stereochemistry (i.e., (S)) using well-known methods, for example, by inversion.
4(3H)-Pyrimidinones:
For the synthesis of 4(3H)-pyrimidinones II (or its tautomer, 4-hydroxy-pyrimidines), the approach displayed in Scheme 1 may be followed (for a review of synthetic methods see: D. J. Brown, Heterocyclic Compounds: the Pyrimidines, supra). This approach involves the cyclization reaction between: an acrylic acid ester XII and an amidine V followed by oxidation of the resulting dihydropyrimidinone XIII to give II. 
For the synthesis of 2-substituted 5-(4-fluorophenyl)-6-(4-pyridyl)-4-hydroxy-pyrimidines II (Scheme 2), the disubstituted acrylic acid ester XII may be prepared conveniently by condensation of pyridine-4-carboxaldehyde with 4-fluorophenylacetic acid followed by esterification. XII may be reacted with a variety of amidines V at elevated temperature. As a dehydrogenating agent for the conversion of XIII to II, sodium nitrite/acetic acid is suitable. 
Accordingly, further compounds of formula II may be obtained in which R12 is any other heteroaryl ring within the definition of R12 by the appropriate choice of starting material. Such starting materials include but are not limited to 2-methylpyridine-4-carboxaldehyde, 2,6-dimethylpyridine-4-carboxaldehyde (Mathes and Sauermilch, Chem. Ber. 88, 1276-1283 (1955)), quinoline-4-carboxaldehyde, pyrimidine-4-carboxaldehyde, 6-methylpyrimidine-4-carbox-aldehyde, 2-methylpyrimidine-4-carboxaldehyde, 2,6-dimethylpyrimidine-4-carboxaldehyde (Bredereck et al., Chem. Ber. 97, 3407-3417 (1964)). The use of 2-nitropyridine-4-carboxaldehyde would lead to a derivative of formula II with R12 represented by a 2-nitro-4-pyridyl group. Catalytic reduction of the nitro to an amino group would provide the 2-amino-4-pyridyl derivative of II. The approach displayed in Scheme 2 is applicable to the use of other aryl aceticacids leading to compounds of formula II with different aryl groups as R11.
Pyrimidinone II (R1xe2x95x90H) may be substituted at the N-3 position by reaction with e.g. an alkyl halide, such as methyl iodide or ethyl bromide in the presence of an appropriate base such as potassium carbonate and the like. 
Another approach (Scheme 3) leading to 5,6-diaryl-4-hydroxy-pyrimidines involves the cyclization of the b-keto ester XIV with thiourea to give the thiouracil derivative XV. XV can be S-monomethylated to XVI. Reaction of XVI with primary and secondary amines leads to 2-amino substituted 4-hydroxy-pyrimidines II. Further 2-thioether derivatives of II with R1xe2x95x90SR21 can be obtained, for example by alkylation of XV with alkyl halides. Treatment of XV or XVI with Raney nickel and H2 provides compounds of structure II wherein R1 is H.
Although Scheme 3 illustrates syntheses in which R12 is 4-pyridyl, this approach may be equally applied to any other heteroaryl ring within the definition of R12 by the appropriate choice of the starting material. Such starting materials include but are not limited to ethyl 2-methyl isonicotinate (Efimovsky and Rumpf, Bull. Soc. Chim. FR. 648-649 (1954)), methyl pyrimidine-4-carboxylate, methyl 2-methylpyrimidine-4-carboxylate, methyl 6-methylpyrimidine-4-carboxylate and methyl 2,6-dimethylpyrimidine-4-carboxylate (Sakasi et al., Heterocycles 13, 235 (1978)). Likewise, methyl 2-nitroisonicotinate (Stanonis, J. Org. Chem. 22, 475 (1957)) may be reacted with an aryl acetic acid ester followed by cyclization of the resultant b-keto ester with thiourea analogously to Scheme 3. Subsequent catalytic reduction of the nitro group to an amino group would give a pyrimidinone II in which R12 is represented by a 2-amino-4-pyridyl group (Scheme 4). 
Furthermore, methyl 2-acetamido isonicotinate (Scheme 5) may be reacted analogously to Scheme 3 after appropriate protection of the amide nitrogen with e.g. a tert-butyldimethylsilyloxymethyl group (Benneche et al., Acta Chem. Scand. B 42 384-389 (1988)), a tert-butyldimethylsilyl group, a benzyloxymethyl group, a benzyl group or the like (P1). 
Removal of the protecting group P1 of the resulting pyrimidine II with a suitable reagent (e.g., tetrabutylammonium fluoride in the case where P1 is t-butyldimethyl-silyloxymethyl) would then lead to a pyrimidinone II with R12 represented by a 2-acetamido-4-pyridyl group. Needless to say, ethyl p-fluorophenyl acetate may be substituted by any alkyl arylacetate in the procedure illustrated in Scheme 3 thus providing compounds of formula II with different R11 aryl substituents.
In a further process, pyrimidinones II may be prepared by coupling a suitable derivative of XVIII (L is a leaving group, such as halogen radical and the like) with an appropriate aryl equivalent. 
Such aryl/heteroaryl couplings are well known to those skilled in the art and involve an organic-metallic component for reaction with a reactive derivative, e.g., a halogeno derivative, of the second compound in the presence of a catalyst. The metallo-organic species may be provided either by the pyrimidinone in which case the aryl component provides the reactive halogen equivalent or the pyrimidinone may be in the form of a reactive 5-halogeno derivative for reaction with a metallo organic aryl compound. Accordingly, 5-bromo and 5-iodo derivatives of XVIII (Lxe2x95x90Br, I) may be treated with arylalkyl tin compounds, e.g., trimethylstannylbenzene, in an inert solvent such as tetrahydrofuran in the presence of a palladium catalyst, such as di(triphenylphbsphine) palladium (II) dichloride. (Peters et al., J. Heterocyclic Chem. 27, 2165-2173, (1990). Alternatively, the halogen derivative of XVIII may be converted into a trialkyltin derivative (Lxe2x95x90Bu3Sn) by reaction with e.g. tributylstannyl chloride following lithiation with butyllithium and may then be reacted with an aryl halide in the presence of a catalyst. (Sandosham and Undheim, Acta Chem. Scand. 43, 684-689 (1989). Both approaches would lead to pyrimidines II in which R11 is represented by aryl and heteroaryl groups.
As reported in the literature (Kabbe, Lieb. Ann. Chem. 704, 144 (1967); German Patent 1271116 (1968)) and displayed in Scheme 6, 5-aryl-2,6-dipyridyl-4(3H)-pyrimidinones II may be prepared in a one step synthesis by reaction of the cyanopyridine with an arylacetyl ester, such as ethyl phenylacetate in the presence of sodium methoxide. 
In Scheme 7, compounds of the present invention of formula XXX can be readily prepared by reacting the methylthio intermediate XXXI with the amine NHR5R21, for example by heating the mixture preferably at a temperature greater than 100xc2x0 C., more preferably 150-210xc2x0 C. Alternatively, compounds of formula XXX can be readily prepared by reacting the methylsulfonyl intermediate XXXII with the amine NHR5R21, for example by heating the mixture preferably at a temperature greater than 40xc2x0 C., more preferably 50-210xc2x0 C. 
Amines of formula NHR5R21 are commercially available or can be readily prepared by those skilled in the art from commercially available starting materials. For example, an amide, nitro or cyano group can be reduced under reducing conditions, such as in the prescence of a reducing agent like lithium aluminum hydride and the like, to form the corresponding amine. Alkylation and acylation of amino groups are well known in the art. Chiral and achiral substituted amines can be prepared from chiral amino acids and amino acid amides (for example, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and the like substituted glycine, xcex2-alanine and the like) using methods well known in the art, such as H. Brunner, P. Hankofer, U. Holzinger, B. Treittinger and H. Schoenenberger, Eur. J. Med. Chem. 25, 35-44, 1990; M. Freiberger and R. B. Hasbrouck, J. Am. Chem. Soc. 82, 696-698, 1960; Dornow and Fust, Chem. Ber. 87, 984, 1954; M. Kojima and J. Fujita, Bull. Chem. Soc. Jpn. 55, 1454-1459, 1982; W. Wheeler and D. O""Bannon, Journal of Labelled Compounds and Radiopharmaceuticals XXXI, 306, 1992; and S. Davies, N. Garrido, O. Ichihara and I. Walters, J. Chem. Soc., Chem. Commun. 1153, 1993 .
Pyridones:
As displayed in Scheme 8, a suitable route to 2(1H)-pyridones III involves the cyclization reaction between an a,b-unsaturated ketone XXII and a sufficiently reactive, substituted acetamide in the presence of base (El-Rayyes and Al-Hajjar, J. Heterocycl. Chem. 21, 1473 (1984)) and subsequent dehydrogenation. 
Accordingly (Scheme 9), pyridine-4-carboxaldehyde or other heteroaromatic carboxaldehyde-like pyrimidine-4-carboxaldehydes or quinoline-4-carboxyaldehydes may be reacted with acetyl aryl, acetyl heteroaryl or acetyl cycloalkyl derivatives in the presence of piperidine/acetic acid at elevated temperature (Bayer and Hartmann, Arch. Pharm. (Weinheim) 324, 815 (1991)) as well as pinacolone (CH3xe2x80x94COxe2x80x94C(CH)3)3) in the presence of sodium hydroxide to provide the unsaturated ketone XXII (or the analogous ketone from the corresponding heteroaromatic-4-carboxyaldehyde). The reaction of XXII with phenylacetamide in the presence of sodium ethoxide then may lead via the 3,4-dihydropyridone to 6-substituted 3-phenyl-4-(heteroaryl)-2(1H)-pyridones of structure III.
In Scheme 10, a feasible route is illustrated leading to 6-chloro-2(1H)-pyridone XXIV, a versatile intermediate for further modifications at the 6-position. This approach (G. Simchen, Chem. Ber. 103, 389-397 (1970) is based on the conversion of the unsaturated g-cyanocarboxylic acid chloride XXIII into XXIV in the presence of hydrogen chloride. 
Reaction of XXIV with ammonia (Katritzky and Rachwal, J. Heterocylic Chem. 32, 1007 (1995)), primary and secondary amines would lead to 2-amino substituted pyridones III. Furthermore, XXIV may be reacted in a palladium or nickel catalyzed cross-coupling reaction with an alkyl or aryl boronic acid or an alkyl or aryl zinc halide to provide pyridone III wherein R3 is alkyl or aryl or heteroaryl.
In addition, pyridone III may be substituted at the N-1 position by reaction with, e .g., an alkyl halide in the presence of an appropriate base such as potassium carbonate.
An approach that may lead to a pyrimidinone of the general formula III is illustrated in Scheme 11. 
According to this approach (Shaw and Warrener, J. Chem. Soc. 153-156 (1958); Hronowski and Szarek, Can. J. Chem. 63, 2787 (1985); Agathocleous and Shaw, J. Chem. Soc. Perkin Trans. I, 2555 (1993)), an ethoxyacryloyl isothiocyanate XXVI is reacted with a primary amine to give as an addition product the acylthiourea XXVII which can be cyclized under basic or acidic conditions to the thiouracil compound XXVIII. XXVIII may be methylated to the methylthio derivative XXIX, a versatile intermediate for further transformations at the 2-position.
Fused 4(3H)-Pyrimidinones:
As displayed in Schemes 12 and 13, introduction of a suitable R4 group through the alkylation of XXXIII affords an intermediate to the fused 5, 6, or 7 membered ring systems of Formula I wherein R1 and V or W are joined. The synthesis utilizes a haloalkylamine in which the amino group is protected through reaction with 1,2-bis(chlorodimethylsilyl)ethane affording the cyclic stabase derivative (see: Basha and Debernardis Tetrahedron Lett 5271, 1984) which protects the amine in the subsequent alkylation step (sodium hydride, DMF). 
Deprotection of the amine can be accomplished with acid treatment (p-toluenesulfonic acid) or tetrabutylammonium fluoride treatment. The free amine can then be cyclized in an intramolecular fashion by warming to high temperatures. The bromoalkylamines are either commercially available (eg. 3-bromopropylamine hydrobromide, 2-bromoethylamine hydrobromide) or they can be synthesized from the corresponding haloalkylazide followed by reduction of the azide to the amine (see: Hendry et al Tetrahedron Lett 4597 (1987)). More functionalized haloalkylamines can be used as long as the functional groups are tolerated in the transformations shown in scheme 12 including the bromo derivatives obtained from amino acid precursors as described by Baldwin et al (Synlett. 51-53, 1993) and Leanna et al (Tetrahedron Lett. 4485, 1993).
Alternatively, the fused ring system can be made through the addition of a hydroxyalkylamine as outlined in Scheme 14. Initially, the amine component of the hydroxyalkylamine displaces the 2-methylthio group to afford compound XXXVII which is followed by conversion of the alcohol to a suitable leaving group (eg. methanesulfonate or trifluoromethanesulfonate). Closure of the ring can be accomplished by treatment with an excess of sodium hydride in DMF to afford XXXVI. 
The 6,5 fused ring systems can be obtained as outlined in Scheme 15. Alkylation of the N-3 nitrogen with 3-bromo-1-trimethylsilylpropyne can be followed by a displacement of the 2-methylthio group with the appropriate amine component exemplified but not limited to a phenylalkylamine. The 2-amino group under the reaction conditions cyclizes onto the acetylene as shown with a loss of the trimethylsilyl group as well. This transformation is illustrated in the examples below wherein 3-phenyl-1-propylamine and benzylamine are reacted with 3-(3-trimethylsilyl-2-propynyl)-5-(4-fluorophenyl)-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone to afford the corresponding6, 5 fused system. 
Compounds of the invention when U is CHR21 can be prepared according to Scheme 2 above wherein R1 contains an leaving group or a group which can be converted into a leaving group (L*) which can be reacted with a primidine nitrogen atoms to form the fused ring (see Scheme 16).